Methods Patients with SVG lesions were randomized to SES or BMS. All were scheduled to undergo 6-month coronary angiography. The primary end point was 6-month angiographic in-stent late lumen loss. Secondary end points included binary angiographic restenosis, neointimal volume by intravascular ultrasound and major adverse clinical events (death, myocardial infarction, target lesion, and vessel revascularization).

Conclusions Sirolimus-eluting stents significantly reduce late loss in SVG as opposed to BMS. This is associated with a reduction in restenosis rate and repeated target lesion and vessel revascularization procedures. (The RRISC Study; http://clinicaltrials.gov/ct/show; NCT00263263).

Saphenous vein grafts (SVGs) remain the most frequently used conduits in coronary artery bypass graft surgery (1). However, within a decade after surgery, one-half of the SVGs develop significant atherosclerotic disease, and recurrent angina after bypass surgery is a common clinical problem (2). Repeated bypass surgery is technically more challenging than the first operation, and it is associated with greater morbidity and mortality; thus, currently percutaneous coronary intervention (PCI) is the preferred treatment for SVG lesions (3,4). Specifically, the implantation of bare-metal stents (BMS) is the actual strategy to treat these patients (5,6). However, the results of BMS in SVGs are less favorable than those in native vessels, with restenosis rates exceeding 30% (5,7).

The introduction of sirolimus-eluting stents (SES) recently has reduced the occurrence of angiographic restenosis and repeated revascularization with respect to BMS in native coronary artery disease (8,9). Despite the growing evidence of the benefits of SES in several subsets of lesions (10–14) and patients (15,16), SVGs have always been excluded from these randomized trials, and currently available registries on SES in SVG offer inconsistent results (17–21). Thus, the aim of our study was to assess whether the use of SES improves angiographic and clinical outcomes when compared with BMS in patients with diseased SVGs.

Methods

The RRISC (Reduction of Restenosis In Saphenous vein grafts with Cypher sirolimus-eluting stent) trial is a randomized double-blind nonindustry-sponsored trial performed in a single center with large experience in the percutaneous treatment of SVG disease (22,23). The trial design was approved by the ethics committee of AZ Middelheim Hospital.

Patient population

Patients were included if they were 18 to 85 years old, had a history of previous coronary artery bypass surgery, had stable or unstable angina, and had one or more “de novo” target lesions (>50% diameter stenosis by visual estimate) localized in one or more diseased SVG with a reference vessel diameter (RVD) >2.5 and <4.0 mm. Exclusion criteria were myocardial infarction (MI) within the previous 7 days (with creatine kinase-myocardial band elevation >2 times the upper limit of normal), documented left ventricular ejection fraction <25%, impaired renal function (creatinine >3.0 mg/dl), distal graft anastomotic stenosis, totally occluded SVGs, previous brachytherapy treatment in the index vessel, or and allergy to aspirin, clopidogrel, heparin, stainless steel, contrast agent, or sirolimus. Aorto-ostial location and thrombotic and/or calcified lesions were not considered exclusion criteria. All enrolled patients provided written informed consent before the index procedure.

Procedural protocol

After percutaneous access was obtained, heparin was administered to maintain an activated clotting time >250 s. Glycoprotein IIb/IIIa receptor blockers were given at operator’s discretion. The use of a distal protection device (GuardWire, Medtronic, Minneapolis, Minnesota) was strongly recommended. After successful crossing of the target lesion with the guidewire, patients were allocated randomly in a 1:1 ratio to treatment with Cypher SES or BX-Velocity BMS (both from Cordis, Johnson & Johnson, Warren, New Jersey). In case of treatment of more than one lesion, the stent type remained the same. Direct stenting was promoted. In case of dissection or incomplete lesion coverage, the use of additional stents of the same type as the assigned stent was mandated. Angiographic success was defined as implantation of the study device with residual diameter stenosis <30% and normal (Thrombolysis In Myocardial Infarction-3) coronary blood flow. Aspirin (100 to 300 mg/day) was given daily, and clopidogrel (loading dose of 300 mg, 6 to 48 h before the procedure and 75 mg/day thereafter) was administered for 2 months in all patients. Serial blood samples for creatine kinase, creatine kinase-myocardial band and cardiac troponin I were routinely obtained before the procedure and at 8, 16, and 24 h after the intervention.

Randomization and blinding process

The randomization process was unblocked and nonstratified. The randomization list was generated by a computer. Randomization was performed by means of opaque envelopes (concealed until the operator successfully wired the target vessel) containing a letter (i.e., “A” or “B”). Because the standard package of the stents is the only visible difference between the two stent types, additional external packages, labeled respectively with “A” or “B” and the specific stent measure, were used. The appearance of the 2 stent types, once the standard package was opened, was the same because the delivery system, the shaft, the stent design, and the measures available were the same for both. After randomization, the interventional staff left the catheterization laboratory, and an independent nurse opened the package of the stent selected from randomization and left the stent on the catheterization table. Thus, the operator (and his staff) and the patient were unaware of the stent type.

Clinical, angiographic, and intravascular ultrasound (IVUS) follow-up

Patients were evaluated clinically 1 and 6 months after the procedure. Coronary angiography was repeated at 6 months (±15 days) and IVUS analysis was recommended in every SVG treated with a study stent. Intravascular ultrasound was performed after injection of 0.2 mg of nitroglycerin with a 30-MHz ultrasound probe (Ultracross 2.9F, Boston Scientific Corporation, Natick, Massachusetts), connected to the Galaxy ultrasound console (Boston Scientific Corporation), and a motorized pullback (speed: 0.5 mm/s). Angiography was performed earlier if there were recurrent symptoms, but if restenosis was not found during this repeated angiography, a new angiography was performed at 6 months.

Quantitative coronary angiographic analysis

Digital coronary angiograms were analyzed offline by an expert operator blinded to the procedure (with an intraobserver variability for measurements of <5%; range, 2.4% to 9.2%), using a validated automated edge detection system (CAAS II, PIE Medical, Maastricht, the Netherlands). Matched views were selected for angiograms recorded before and immediately after the intervention and at 6-month follow-up. Angiographic measurements were made both in the stent and in the stented segment (defined as the stent plus the 5-mm edges proximal and distal to the stent) during diastole using the contrast-filled guiding catheter for magnification calibration. In case overlapping stents were placed, a single in-stent value was measured, and the segment was considered as the entirely stented part plus the 5 mm proximal to the more proximal stent and the 5 mm distal to the more distal stent implanted. Lesion RVD, minimal luminal diameter (MLD), percent diameter stenosis, and length were obtained at baseline. Reference vessel diameter, MLD, and diameter stenosis were evaluated at the end of the procedure and at follow-up for the in-stent, proximal edge, distal edge, and in-segment sections (24). Acute gain was defined as the difference between the in-stent MLD at the end of the intervention and the MLD at baseline. Late lumen loss was calculated as the difference in MLD between measurements immediately after the procedure and at follow-up. Binary angiographic restenosis was defined as diameter stenosis >50% by quantitative coronary angiography, at the follow-up angiogram (25). Restenosis patterns were assessed using the Mehran classification system (26).

IVUS analysis

Intravascular ultrasound data were stored on S-VHS videotape. The videotapes were transformed into the DICOM medical image standard. Quantitative coronary ultrasound analysis was performed using a validated software (Curad, version 4.32, Wijk bij Duurstede, the Netherlands), allowing semiautomated detection of luminal and stent boundaries in reconstructed longitudinal planes (27). To obtain a smooth appearance of the vessel wall structures in the longitudinal views, the Intelligate image-based gating method was applied (28–30). This validated technique retrospectively selects end-diastolic frames, allowing more reliable volumetric measurements. Volumetric quantitative coronary ultrasound analysis was obtained for stent and lumen. Neointimal volume was computed as the difference between the stent volume and the lumen volume.

End points and definitions

The primary end point of the study was 6-month in-stent late lumen loss. Secondary angiographic end points included in-segment late loss and in-stent and in-segment binary restenosis rate. Secondary IVUS end point was in-stent neointimal volume. The secondary clinical end points were in-hospital, 30-day, and 6-month major adverse cardiac event (MACE) rates. MACE included death, all nonfatal major MI (also periprocedural), and target vessel revascularization (TVR). Major periprocedural MI was defined as an elevation of creatine kinase enzyme-myocardial band activity >3 times above the upper limit of normal (16 U/l in our institution). Nonperiprocedural MI was defined as a new ischemic event with creatine kinase-myocardial band >2 times the upper limit of normal, or the electrocardiographic presence of new pathological Q waves. We also recorded minor periprocedural myocardial damage, defined as a elevation of cardiac troponin I >0.4 ng/dl (31) or, if preprocedural cardiac troponin I was already positive (in unstable patients), doubling of its value at any of the postprocedural samples, without fulfillment of the criteria for major periprocedural MI. Target lesion revascularization (TLR) was defined as a repeated revascularization procedure (either PCI or coronary bypass surgery) due to restenosis in the stented segment. Target vessel revascularization was defined as a new revascularization procedure in the target vessel, including also TLR. Target vessel failure was defined as a composite of TVR, treated vessel-related MI, and cardiac death. Stent thrombosis was defined according to Iakovou et al. (32). All the clinical events were adjudicated by an independent clinical events committee unaware of the patients’ treatment assignment.

Statistical analysis

Sample size was calculated on the assumption that the mean per-lesion in-stent late loss in the BMS group would be 1 ± 0.9 mm. To detect a decrease in mean late loss in the SES group of 0.6 mm, with an 80% power and a 2-tailed type I (alpha) error of 0.05, 35 patients per group were required. Considering a 10% rate of patients with >1 lesion intervention (22,23) and a 15% rate of dropouts, the number of enrolled patients was increased by 8%.

All analyses were conducted according to the intention-to-treat principle. The quantitative angiographic and IVUS results were analyzed on a per-lesion basis, whereas the clinical events were assessed per-patient. Continuous data are expressed as means ± standard deviations or as medians [interquartile range] as appropriate, whereas dichotomous data are summarized as frequencies. Student tor Mann-Whitney Utest (as appropriate) and chi-square or the Fisher exact test (as appropriate) have been used, respectively, for continuous and categorical variables, to analyze differences between the 2 study arms. A linear regression analysis with the primary end point (in-stent late loss) as dependent variable and all the baseline clinical and angiographic characteristics known to influence late loss as independent variables (stent type, maximum balloon diameter, maximum inflation pressure, postdilation performed, total stent length per lesion, diabetes, age of coronary artery bypass grafting, baseline lesion length, baseline RVD) also was performed to confirm the results of our analysis. Relative risks (RRs) with their 95% confidence intervals (CIs) were computed for dichotomous variables. Computation of the number-needed-to-treat (with 95% CI), extrapolated from the absolute risk difference, was made for clinical variables. A 2-sided p value <0.05 was considered significant for all tests.

Results

Study population and procedural outcomes

Between September 2003 and November 2004, 75 patients with 96 lesions localized in 80 SVGs were enrolled (Fig. 1).Baseline clinical characteristics of the patients, as well as the angiographic and procedural characteristics of the lesions treated, are shown in Table 1.The 2 groups were well balanced for all the variables considered. Of a total of 114 stents deployed, 54 were BMS and 60 SES. Angiographic success was achieved in all the lesions treated. The use of glycoprotein IIb/IIIa inhibitors was very low (only in 1 SES patient). Distal protection devices were used in more than 80% of the lesions treated. Only in case of distal position of the stenosis in the vein graft (not enough space for the placement of the device), suboptimal back up of the guiding catheter, or presumed low risk of embolization (very focal lesions), distal protection was not used.

Baseline Clinical and Procedural Characteristics of Patients and Lesions in the Two Groups

Six-month angiographic and IVUS outcomes

None of the patients was lost to follow-up. At 6 months, 3 SES patients did not receive angiographic follow-up. An 83-year-old man with diabetes died 5 months after the procedure because of severe progressive cardiac failure. The other 2 patients refused the control angiography. Both were completely symptom-free and without inducible ischemia at the 6-month clinical visit. Thus, 6-month angiography was performed in 37 (100%) BMS patients and in 35 (92%) SES patients (p = 0.24). An IVUS analysis was performed in 59 patients (81.9% of all the patients receiving angiographic follow up). Overall, 39 lesions were analyzed in the BMS group, whereas 34 lesions were analyzed in the SES group (p = 0.40). Reasons for lack of IVUS follow-up in 13 patients included occlusive or subocclusive in-stent restenosis that prevented a safe passage of the IVUS probe or poor trackability of the IVUS probe in the SVG because of the tortuosity of vessel itself. Patient demographics were not different between those patients with versus without IVUS at follow-up.

Angiographic and IVUS data are presented in Table 2.The primary end point of the study, lesion-based in-stent late loss reduction, was met. Also, the linear regression analysis showed that the only adjusted predictor of in-stent late loss remained the type of stent used (p = 0.001). Accordingly, SES showed a significant reduction in all other secondary angiographic and IVUS end points on a per-lesion analysis. The RR of in-stent or in-segment restenosis occurrence after SES versus BMS was 0.37 (95% CI 0.15 to 0.97) and 0.42 (95% CI 0.18 to 0.97), respectively. Among the 6 in-segment binary restenoses after SES, 1 occurred in the distal edge, whereas the others were in-stent. Five of 6 were focal (83.3%), and 1 was diffuse (16.7%). No SES-restenotic occlusion was detected. Four restenoses (66%) occurred when multiple SES were deployed to cover one lesion. All the 16 in-segment binary restenoses after BMS were in-stent, apart from 1 that occurred in the proximal edge. After BMS implantation, most restenoses (62.5%) had a non-focal pattern: 7 diffuse (43.8%), 1 proliferative (6.3%), and 2 occlusive (12.5%).

Quantitative Coronary Angiography and Intravascular Ultrasound Volumetric Analysis of Lesions Treated in the Two Groups

In-hospital, 1-month, and 6-month clinical outcomes

Clinical events are presented in Table 3.No deaths or urgent revascularizations occurred during hospitalization. The rate of major periprocedural MI was 4%, whereas minor myocardial damage occurred in 17.3% of the patients, without differences between BMS and SES patients (see Table 3for details). Between the end of the hospitalization and the first month after treatment no further events were recorded.

After 35 days, 1 MI occurred in a SES patient because of the occlusion of a vein graft other than the one treated in the index procedure. After 5 months, a patient in the SES group died, as previously described. The rates of TLR and TVR (all ischemia-driven PCI, namely PCI performed because of anginal complains or evidence of myocardial ischemia at exercise or pharmacological stress test) were significantly reduced after SES with respect to BMS: 5.3% versus 21.6% (p = 0.047) and 5.3% versus 27% (p = 0.012), respectively. The RR for TLR was 0.24 (95% CI 0.05 to 1.0), whereas for TVR it was 0.19 (95% CI 0.05 to 0.83). Number-needed-to-treat calculation showed that assigning 6 (3 to 175) patients to SES prevents a TLR with respect to BMS. Moreover, 5 (2 to 19) patients should be treated with SES to prevent a TVR. All TVR occurred at 6 months apart from 2 in the BMS group (1 at 2 months and 1 at 4 months); furthermore, 2 patients who received BMS underwent TLR in 2 lesions each. Indeed, on a per-lesion analysis the RR of TLR was 0.21 (95% CI 0.05 to 0.90). The cumulative MACE rate was not different between the 2 groups. No stent thrombosis was recorded.

Discussion

Recurrent angina after coronary artery bypass surgery is a common clinical problem. Within 10 years after the operation, half of all SVGs are totally occluded or have severe atherosclerotic disease (2). Although the implantation of BMS is the actual percutaneous strategy to treat patients with SVG lesions, the incidence of angiographic restenosis and repeated revascularization remains high (5,7,19). Implantation of SES has the potential to become the new therapeutic approach (19,20), but there has been no prospective comparison of BMS and SES in SVGs.

Our study is the first randomized comparison of SES versus BMS in patients with diseased SVGs. Our data show that in this challenging setting the use of SES effectively reduces late lumen loss when compared with BMS. Late lumen loss has been extensively used in interventional cardiology trials as a reliable end point for 2 reasons. First, late lumen loss is a surrogate for in-stent neointimal hyperplasia (which is the pathological process that can lead to in-stent restenosis) (33). Accordingly, our IVUS data demonstrate that SES efficiently inhibits neointimal hyperplasia in SVG: a complete absence of neointimal growth was evident in 47% of the SES lesions versus only 2.5% of the BMS lesions. Second, recent data have shown that late lumen loss is a robust parameter to compare different types of stents and to predict binary angiographic and clinical differences (33,34). Although our study was underpowered to assess clinical end points, the beneficial angiographic and IVUS outcomes translated into a significant advantage in terms of binary restenosis, TLR and TVR, which suggests a clinical benefit for SES over BMS also in diseased SVGs, mainly for a reduced revascularization procedure rate. The finding of relative risk reductions of approximately 60% for restenosis and of around 80% for repeated revascularization further substantiates this benefit, as these values compare well with those obtained in trials performed in native coronary arteries (8–16).

Our trial is the first randomized study to date performed in de novo SVG lesions to show a significant angiographic benefit. Neither the pivotal Saphenous Vein De novo trial nor the recent Venestent trial were able to show a significant reduction in binary angiographic restenosis (which was the primary end point of both studies) of BMS versus balloon angioplasty (5,6). Furthermore, in these 2 trials, the late loss of BMS was comparable with that of balloon angioplasty, if not worse. Other devices have been recently tested in diseased SVG, with disappointing results (35,36). Membrane-covered stents have been proposed as new option to reduce the restenotic process (35), but results from several randomized trials failed to show a significant benefit over standard BMS (36–38). In percutaneous SVG treatment, only the WRIST SVG (Washington Radiation for In-Stent Restenosis Trial for Saphenous Vein Graft) study showed a significant reduction of all the angiographic and clinical end points adding radiation therapy to conventional treatment (39). However, this trial assessed only in-stent restenotic SVG lesions; thus, its results cannot be extrapolated to de novo SVG lesions.

External validity

Several issues remain to be evaluated. First, the possible risk of late stent thrombosis, which has been already shown for native coronary arteries (40,41), also should be considered in a potentially favorable milieu such as SVG. Indeed, plaques in SVGs are lipid-rich, soft, and more prone to rupture than plaques in native coronary arteries (42). In addition, the histopathology of SVG after stent implantation is a mixture of cellular hyperplasia, progression of atherosclerosis, local inflammatory reaction to metallic stent struts, and thrombosis (43,44). Second, longer-term outcomes also may be compromised by late SES restenosis, a phenomenon that was recently described in native coronary arteries (45) and that can be potentially exacerbated by the specific pathology of SVGs. Finally, because of the exclusion criteria of our trial, our data do not apply to large SVGs (with RVD >4.0 mm), to in-stent restenotic lesions, to occluded vein grafts, to lesions localized in the distal vein graft anastomosis, and to patients treated for acute MI related to a sudden SVG occlusion.

Study limitations

The main limitations of our study are inherent to the monocentric design and the small sample size, which was underpowered for major clinical end points and led to broad confidence intervals for the assessment of the relative risks and the number needed to treat for repeated revascularization procedures. Therefore, the possible existence of type I (alpha) or II (beta) error for all the secondary end points should not be dismissed. In particular, the rate of periprocedural myocardial damage (as assessed by troponin elevation) was more than double after SES, despite this increase was nonsignificant.

In light of the nondefinitive clinical results of this trial, we welcome future larger trials, with a multicenter design, to unquestionably show a clinical benefit of SES in SVG with respect to BMS. In particular, these trials should mainly focus on potentially harmful events, such as late restenosis and stent thrombosis.

Conclusions

Our study has shown that, in diseased SVGs, SES significantly reduce 6-month angiographic late lumen loss as opposed to BMS. This reduction is associated with a reduction in binary restenosis rate and repeated target lesion and target vessel revascularization procedures.

(2002) Randomized Study with the Sirolimus-Coated Bx Velocity Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions: A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med346:1773–1780.

(2000) Myocardial infarction redefined—a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J21:1502–1513.

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